Preparation of racemic santonin



United 1 PREPARATION OF RACER lit: SANTONIN Yasuo Abe, Theda, Osaka,Tadats" tau, Kyoto, Hisashi Ishilrawa, Kobe, Talzuichi Milo, Amagasakl,Hyogo, Masao o mi, Iheda, ()saka, and Tadashi Togo, Ashiya, Hyogo,.fapan, assignors to Takecia Pharmaceutical industries, Ltd Higashi-ku,Osaka, Japan No Drawing. Application April 19, 1954 Selim No. 424,284

Claims priority, application Japan September 36 1953 6 Claims. (Cl.Zea-343s This invention relates to optically active and inactivestereoisomers of santonin.

The isomers have the common structure representable by the foltowingformula:

I I CH3 O Patented IE-lay T? ind The 4 racemates in the presentinvention are explained as follows:

(A) The optically inactive stereoisomeride consisting of equivalentamounts of ii id. it is design ted as racemic santonin C. a

(B) The optically inactive stereoisomeride consisting of equivalentamounts of ill and lid. It is designated as racemii santonin D.

(C) The optically inactive stereoisomeride consisting of equivalentamounts of H11 and Hid. It is designated as racemic oc-SflfllOHlH.

The iiy inactive stereoisorneride consisting of equivalent amounts of1V1 and Did. It is designated as racemic ,B-santonin.

The 2 optically active isomers in the present invention are explained asfollows:

(E) The optically active compound representable by the Formula Hid. itis designated as dextrorotatory ccsantonin'.

(F) The optically active compound representable by the Formula lVd. Itis designated as dextrorotatory 18- santonin.

in general these compounds are almost insoluble in water, sparinglysoluble in ether and petroleum, but they are soluble in a variety of hotorganic solvents, such as methanol, ethanol, chloroform, ether, benzene,acetone and petroleum etc, and in aqueous solution of alkali.

These compounds as a whole show the absorption band characteristic ofe,;3,[3-trisubstituted ot,fi-I1I1S8.tl1l2.td ketone in the ultra-violetregion. They are effective as anthelmintic and in some of them theactivity is almost equal to that of natural sautonin. Many of them areless toxic than natural santonin and some of them show half the toxicityof natural santonin.

By the action of sodium methylate in methanol all these compoundsdisplay the pink color characteristic of natural santonin, but the colorreaction is rather weak in the case of santonin C or D.

Next, detailed explanations are made. on the individuals of thecompounds.

(a) Racemic santonin C is recrystallized from methanol into colorlessprisms, M. P. C. When subjected to dienone-phenol rearrangement byheating with 55% sulfuric acid at 50 C., it is converted into rac.u-desmotroposantonin, M. P. 198 C. The ultra violet spectrum of thecompound has an absorption maximum at 247 my. (log 6 4.15) but it showsno such a characteristic shoulder in the vicinity of 270 ru as is seenin natural santonin.

(b) Racemic santonin D is recrystallized from methanol into colorlessprisms, M. P. C. This compound has an absorption maximum at 245 m (10g 64.19)- When subjected to rearrangement with 55% sulfuric acid, it isconverted into racemic B-desmotroposantonin, M. P. 232 C.

(c) Racemic a-santonin is recrystallized from methanol into colorlessplates, M. P. 181 C. This compound has an absorption maximum at 241 m(log 4.28) and shows a shoulder in the vicinity of 270 m in accordancewith those of natural santonin. The infra-red spectra of this compoundalso well accord with those of natural santonin. When subjected toclienone-phenol rearrangement by heating with 55% sulfuric acid at 50C., it is converted into racemic a-desrnotroposantonin.

(d) Racemic S-santonin is recrystallized from methanol into colorlessrhombic plates, M. P. 186 C. This compound has an absorption maximum at242 m (log. e=4.19) and show a characteristic shoulder in the vicinityof 270 m n. The infra-red spectra of this compound well accord withthose of natural santonin. Both the ccand B-santonins are racemateswhich correspond to natural 'a-santonin and natural fl-santonin,respectively. When spectra of this compound Well accordwith those ofnatural santonin. The specific rotatory power of this compound is [a]=+l68 (2% solution in alcohol) and it is the antipode of naturall-a-santonin. This compound is converted into d-a-desmotroposantorinthrough the dienone-phenol rearrangement.

(f) Dextrorotatory-fi-santonin or (+)-,8-santonin is recrystallized frommethanol into colorless prisms, M. P.

215 C. The specific rotatory power of this compound is E J Q=+I37 (2%solution 'inchloroform) and it is the antipode of natural p-santonin.This compound is converted into d-fi-desmotroposantonin through thedienone-phenol rearrangement. e

'I 'he-methods'for manufacturing them are explained as follows: (a)Rac.-santonin C,-The l/iichaelcondensationof 3- keto'-4,9-dimethyll,2,3,7,8,9-hexahydronapthalene vdiethylmethylmalonate in thepresenceofsodium methylate gave rac.-diethyl(3-keto-4,9-dimethyl-1,2,3,5,6,7,8,9-octahydro-fi-naphthyl) -methyhnalonate, which, on alkaline hydrolysis (the free acid melts at 204C. with decomposition) and subsequent decarboxylation, yielded a mixtureof substituted propionic acids epimeric at C An isomer of v"racl-a-(3-keto-4,9-dimethyl-l,2,3,5,6,7,8,9-octahydro-' 6-napthyl)-propionic acid, M. P. 135 C. (designated as D-acid) was obtained byrecrystallization from ethyl acetrite-petroleum. ether and subsequentlyfrom methanol- 'water. The mother liquors of the ethyl acetate-petroleumether recrystallization were concentrated and the separatingcrystallinematerial was recrystallized from methanol-water to atfordanother. lSOlTEY'Of. the acid, M. 'P.

with

145 f C. (designated as C-acid). Bromination of C-acid gave the lactoneof rad-a-('3-keto-2-bromo-4,9-dimethyl-S-hydroxy-1,2,3,5,,7,8,9-0ctahydro-6-naphthyl -propionic acid, M. P. 145C. (dec.),.and this was dehydrobrominated vith boiling'collidine torac.-santonin C, M. P. 180

(b Rac.-sqnt9nin D.-.-Rac.-santonin D was prepared from rac.-D-acid, M.R135? C., by the same procedure '.as describedon the;precedingexperiment for rac.-santonin C via bromolactone D.(M..P. 143 C. dec.).This was recrystallized from "methanol to colorless prisms, M.P.190 C. g

(c) Racwfi-santoninf. To a solution of rac.-C- and -D- a'cidIin glacialacetic acid, selenium dioxide and a small amount of water was added andrefluxed for 4 hours. 'The precipitating selenium was filtered off, andthe filtrate was distilled ata reduced pressureIfIhe residue was ex-'tracted with ether,'and theether extract was washed with sodiumcarbonate solution and water successively, and dried over anhydroussodium sulfate. On evaporation of the ether, a crystalline materialseparated from the residue, which on recrystallization from methanolgave colorless prismsof rac.-;8-santonin, M. P. 186 C.

(d) Ram-oc-santofiinE-Ffom the mother liquor of rac.-

B-santonin, described in the preceding example, was obtained anothercrystalline product, viz., rac.-asantonin.

This was recrystallized from aqueous methanolas colorless rectangularplates, M; P. 181 C.

Resolution of this dienone-acid was effected via the brucine or quinonesalt, and the laevo acid thus obtained was decarboxylated to an isomericmixture of two optically activeu-(3-l:eto-4,9-dimethyl-3,5,6,7,8,9-hexahydrov 6-naphthyl)-propionicacids epimeric at C This. material was boiled with selenium dixode inacetic acid for several hours. After precipitatingselenium was removedby filtration, and the solvent was evaporated to leave a crude mixtureof 'diand d-p santonin.

When heated with methanolic potassium hydroxide,

the crude santonin isomers were changed to a mixture of thecorresponding potassium-santoninates. The solution was acidified withhydrochloric acid, and d-u-santonin was obtained from the easilylactonizing part; as colorless rectangular plates, M. P. 172 C.

(7) d-e-Santonin 0r (+)-fl-sar zt0nin.The velocity of lactonization ofd-jS-santoninic acid is slower than that of d-a-isomer. V

After d-a-santonin was removed in the manner described in Example 2, theacidified solution was warmed on the water bath affording d-p-santoninas colorless rhombic prisms, M. P. 215 C. a All melting points areuncorrected.

This invention also relates to a process for preparing racemic santoninD.

That is, hydrolysis of racemic a-(3 -keto-4,9-dimethyl-1,2,3,5,6,7,8,9-octahydro-6-naphthyl)-propionic acid alkyl ester (V)prepared by the method given in Proceeding of the Japan Academy 28, 425(1952) and J. Am. Chem. Soc. 75, 2567 (1953), gives anisorneric mixture,from which two isomers, racemic a-(3-keto-4,9-dimethyl-l,2,3,-

-5,6,7,8,9-octahydro-6-naphthyl)-propionic acid-A (VTa: designated asA-acid, M. P. 181 C.) and -B (VIb: desig-' nated as B-acid, M. .P.l20125 C), were crystallized. Exhaustive separation of the A and B acidsleaves behind anacidic substance containinganother .acid, M. P. C.(Vldz' designated asv Dracid) and-halogenation of the substance by twomoles of halogen or by the Wohl- Zieglers procedure for allylhalogenation with two moles of reagent yields racemica-.(3-keto-4,9-dimethyl-2-halogeno-5-hydroxy-l,2,3,5, 6,7,8,9 octahydro6 naphthyl)- propionic acid lactone (VII). v V a a As halogenating agentby the Wohl-Zieglers method are cited, for example, N-succinicimidobromide, N-phthalic' imidobromide, N-succinic imidochloride andN-phthalic.

imidochloride. v a

In the above mentioned halogenation of D-acidracemic a-(3-leto-4,9-dimethyl-2,5-dihalogeno-l,2,3,5,6,7,8,9octahydro-6-naphthyl)-propionic acid is isolated as an intermediate insome experiments, but treatment of this compound with a basic reagentsuch as carbonates of alkali and alkaline earth metal gives rise to thehalogenolactone (VII) under splitting off the halogen at C with thehydrogen of the carboxyl atC as hydrogen halide.

0n the other hand, the C -halogeno-lactone (VII) is a also obtained bymono halogenation of D-acid (VId: M. P. 135 C.) toforma-(3-l;eto-4,9-dirnethyl-5-hydroxy-1,2,3,5,6,7,8,9-octahydro-6-naphthyl)-propionic acid lactone.(VIII)'followed by halogenation at C Treatment of the halogenolactone(VII) with a basic reagent, for example, collidine, pyridine,piperidine, picoline, N,N-dialkylaniline, primary or secondary amine,silver oxide, carbonates and bicarbonates, of alkali and alkaline earthmetal or neutral salts such as lithium chloride, magnesium chloride indimethyl formamide, introduces a double bond between C and C producingthe desired product, racemic santonin D. This product, M. P.

C., has absorption maximum at 245 na .(log

.C, 73.14; H, 7.37. p

The reactions in this invention are shown in the following scheme:

(V) OH:

(R=alkyl radical) O= (|]CH;

C O O R CH:

(V18) CH; (V (Vld) H O +CH: Y C O OH CCH3 I CH3 0-C 0 (VIII) (VII) CH;

i 0- 0-0 HI 0 E: C O (X =halogen) (IX) OH:

H O JCH:

a. at.

All melting points are uncorrected.

Example 1 Twenty-five grams of the mother liquors of rac.-A- and -B-acid(of. Proc. Japan Acad. 28, 425 (1952); I. Am. Chem. Soc. 75, 2567(1953)), in 250 cc. of ether were agitated, and to this was graduallyadded a solution of 48 g. of bromine in 250 cc. of acetic acid at roomtemperature. The ether was removed under reduced pressure and theresidue poured into a large quantity of water, extracted with ether, andthe ether solution was Washed with water, sodium bicarbonate and wateragain. After being dried over sodium sulfate, the solution wasconcentrated to leave a small amount of ether. Filtration gave 0.7 g. ofcrystalline substance, which was recrystallized from methanol to affordthe lactone of rac. lit-(3-keto-4,9-dimetl1yl-2-bromo-5-hydroxy-1,2,3,5,6,7,8,9-octahydro-6-naphtl1yl)-propionicacid (VII) as colorless plates, M. P. 180 C. dec.

A mixture of 0.7 g. of the above lactone and cc. of 'y-collidine washeated at 140-150 C. for an hour. The reaction mixture was cooled, takenup in ether, and the ether solution was washed with water, dilutedsulfuric acid, water, sodium carbonate and Water by turns, dried andevaporated. The crystalline material was filtered and 6 recrystallizedfrom methanol to furnish the lactone of rac.u-(3-keto-4,9-dimethyl-3,5,6,7,8,9-heXahydro-6-naphthyl) -propionic acidas prisms, M. P. 190 C., which was designated as rac.-santonin D (IX).

Example 2 To a suspended solution of 4 g. of rac.-D-acid in cc. of ethercontaining a few drops of hydrogen bromideacetic acid, was addeddropwise a solution of 2.6 g. of bromine in 26 cc. of acetic acid. Thesolution was concentrated under reduced pressure and diluted with water.The separating solid was recrystallized from methanol to give 2.5 g. ofthe lactone of rac. a-(3-keto-4,9-dimethyl-5-hydroxy-l,2,3,5,6,7,8,9-octahydro-6-naphthyl) propionic acid D (VIII),M. P. 138 C.

A mixture of 2.5 g. of the lactone D (VIII) in 50 cc. of ether and 1.6g. of bromine in 16 cc. of acetic acid was refluxed for 40 minutes on awater bath. After evaporating the ether, the residual solution wasdiluted to afford 1.0 g. of the lactone of rac.oc-(3-ii'.O-4,9dlmethyl-Z-bromo-S- hydroxy l,2,3,5,6,7,8,9 octahydro--naphthyD-propionic acid D (VII) which was dehydrobrominated torac.-santonin D (IX) in the same way as described in Example 1.

What is claimed is:

l. A method for the manufacture of a racemic santonin having a meltingpoint of C. (uncorr.), which comprises subjecting the lactone of racemicu-(3-keto-4,9-dimethyl-Z-halogeno-S-hydroxyl ,2,3 ,5 ,6,7,8 ,9octahydro-6- naphthyD-propionic acid to the action of adehydrohalogenating agent selected from the group consisting of bases ofthe pyridine series and metal halides, whereby the 2- positioned halogenis split ofl and a double bond is formed between C and C 2. A method forthe manufacture of a racemic santonin having a melting point of 190 C.(uncorr.), which coinprises subjecting racernicix-(3-keto-4,9-dimethyl-1,2,35,- 6,7,8,9-octahydro-6-naphthyl)-propionicacid to the action of two equivalents of free halogen whereby thehalogen is introduced at each of the 2- and 5-positions, and subjectingthe product to the action of a dehydrohalogenating agent selected fromthe group consisting of bases of the pyridine series and metal halideswhereby the halogen at C and the hydrogen of the carboxyl radical at Csplit off as hydrogen halide forming a lactone ring, and the halogen issplit off at C forming a double bond between C and C 3. A method for themanufacture of a racemic santonin having a melting point of 190 C.(uncorr.), which comprises subjecting racemicx(3-keto-4,9-dimethyl-l,2,3,5,- 6,7,8,9-octahydro-6-naphthyl)-propionicacid to the action of one equivalent of free halogen whereby the halogenis introduced at the 5-position, subjecting the product to the action ofa dehydrohalogenating agent selected from the group consisting of basesof the pyridine series and metal halides whereby the halogen at C andthe hydrogen of the carboxyl radical at C split off as hydrogen halideforming a lactone ring, subjecting the product to the action or" oneequivalent of free halogen whereby the halogen is introduced at C andsubjecting the product to the action of a dehydrohalogenating agentselected from the group consisting of bases of the pyridine series andmetal halides whereby the halogen at C is split ott and a double bond isformed between C and C 4. A process according to claim 1, wherein thedehydrohalogenating agent is 'y-collidine.

5. A process according to claim 2, wherein the halogen is bromine andthe dehydrohalogenating agent is y-collidine.

6. A process according to claim 3, wherein the halogen is bromine andthe dehydrohalogenating agent is 'y-collidine.

(References on following page) 7 f References Cited in the file of thispatent Clemo et al.: J. Chem. Soc.', 1952, page.3 843.. Paranjape etal.: Current Science, v91. 12, pages 150- 151 1943).

Abe et al.: Chem. Abst vol. 48, page 1317 (1954), citing Proc. Jap.Acad., v01. 28, pages 425-8 (1952).

Abe et al.: Chem. Abst., vol. 48, pages 10706-10707 (1954), citing Proc.Jap. Acad;, vo1. 29, pages 113-114 Jap., v01. 72, pages 1339- 1342(1952); r

Barnett: Stereochenfistry(l950), pages 3 to 26 '(Pitman and Sons, Ltd.,London).

Fieser and'Fieser: OrganicChemistry (2d ed., 1950), pages 246-277. V

'Karrerz- Organic Chemistry (3rd., 1947), pp. 95-105.

Cohen: Organic Chemistry, part II (4th ed., .1923),

pages 194-9 (Longmans, Green and Co., London); Clemo et al.: Journ.Chem. See, 1934, pages 1343 -6.

Gunstone et al.: Journ. Chem. Soc, 1952, pages 1354- i J. A. C. S. 7 5,pages 2567-2571, June 5,

2. A METHOD FOR THE MANUFACTURE OF A RACEMIC SANTONIN HAVING A MELTINGPOINT OF 190*C. (UNCORR.), WHICH COMPRISES SUBJECTING RACEMICA-(3-KETO-4,9-DIMETHYL-1,2,3,5,6,7,9-OCTAHYDRO-6-NAPHTHYL)-PROPIONICACID TO THE ACTION OF TWO EQUIVALENTS OF FREE HALOGEN WHEREBY THEHALOGEN IS INTRODUCED AT EACH OF THE 2- AND 5-POSITIONS, AND SUBJECTINGTHE PROCUCT TO THE ACTION OF A DEHYDROHALOGENATING AGENT SELECTED FROMTHE GROUP CONSISTING OF BASES OF THE PYRIDINE SERIES AND METAL HALIDESWHEREBY THE HALOGEN AT C5 AND THE HYDROGEN OF THE CARBOXYL RADICAL ATC11 SPLIT OFF AS HYDROGEN HALIDE FORMING A LACTONE RING, AND THE HALOGENIS SPLIT OFF AT C2 FORMING A DOUBLE BOND BETWEEN C1 AND C2,
 3. A METHODFOR THE MANUFACTURE OF A REACEMIC SANTONIN HAVING A MELTING POINT OF190*C. (UNCORR.), WHICH COMPRISES SUBJECTING RACEMICA-(3-KETO-4,9-DIMETHYL-1,2,3,5,6,7,8,9-OCTAHYDRO-6-NAPHTHYL)-PROPIONICACID TO THE ACTION OF ONE EQUIVALENT OF FREE HALOGEN WHEREBY THE HALOGENIS INTRODUCED AT THE 5-POSTION, SUBJECTING THE PRODUCT TO THE ACTION OFA DEHYDROHALOGENATING AGENT SELECTED FROM THE GROUP CONSISTING OF BASESOF THE PYRIDINE SERIES AND METAL HALIDES WHEREBY THE HALOGEN AT C5 ANDTHE HYDROGEN OF THE CARBOXYL RADICAL AT C11 SPLIT OFF AS HYDROGEN HALIDEFORMING A LACTONE RING, SUBJECTING THE PORDUCT TO THE ACTION OF ONEEQUIVALENT OF FREE HALOGEN WHEREBY THE HALOGEN IS INTRODUCED AT C2, ANDSUBJECTING THE PRODUCT TO THE ACTION OF A DEHYDROHALOGENATING AGENTSELECTED FROM THE GROUP CONSISTING OF BASES OF THE PYRIDINE SERIES ANDMETAL HALIDES WHEREBY THE HALOGEN AT C2 IS SPLIT OFF AND A DOUBLE BONDIS FORMED BETWEEN C1 AND C2.